Developmental changes in early postnatal inhibitory circuits in the medial prefrontal
cortex compared to primary somatosensory cortex of the mouse.
The prefrontal cortex (PFC) controls higher cognitive abilities severely impaired in
neurodevelopmental disorders. The PFC is characterised by delayed maturation extending
until the end of adolescence. The cellular mechanisms controlling the early development of
prefrontal circuits are still largely unresolved. Our study delineates the developmental cellular
processes in vitro that are on-going in the mouse medial PFC (mPFC) during the second and
third postnatal weeks (P10 and P20) or neonatal and pre-juvenile periods, respectively, and
compares them to those in the barrel cortex (BC). We show that the basal synaptic
transmission decreases with age as a result of a concurrent reduction of spontaneous
postsynaptic excitatory currents and increase of inhibitory ones. Although total cell density in
the mPFC is decreased from the second to third postnatal week, the number of parvalbumin
(PV) and serotonin receptor (5HT3aR)-positive interneurons is increased. Furthermore, our
data indicate that increased GABAA receptor activity leads to increased basal synaptic
transmission of neonatal mPFC, showing that the effect of GABA is not inhibitory in this time
window in mPFC in contrast to BC. Supporting evidence comes form results describing the
expression of KCC2, an integral transporter involved in the switch between depolarizing and
hyperpolarizing action of GABA. KCC2 levels are decreased in neonatal mPFC compared to
both pre-juvenile PFC and BC at both ages. In parallel, the intrinsic properties of both
interneurons and pyramidal are altered from P10 to P20 in both brain areas. Finally, we show
that all the above developmental events relate to increased network activity in the mPFC from
the second to the third postnatal week, in vivo. Mice with decreased number of interneurons exhibit aberrant spontaneous and
oscillatory activity in the barrel cortex.
GABAergic (γ-aminobutyric acid) neurons are inhibitory neurons and protect neural tissue
from excessive excitation. Cortical GABAergic neurons play a pivotal role for the generation
of synchronized cortical network oscillations. Imbalance between excitatory and inhibitory
mechanisms underlies many neuropsychiatric disorders and is correlated with abnormalities
in oscillatory activity, especially in the gamma frequency range (30-80Hz). We investigated
the functional changes in cortical network activity in response to developmentally reduced
inhibition in the adult mouse barrel cortex (BC). We used a mouse model that displays ~50%
fewer cortical interneurons due to the loss of Rac1 protein from Nkx2.1/Cre-expressing cells
(Rac1 conditional knockout (cKO) mice), to examine how this developmental loss of cortical
interneurons may affect basal synaptic transmission, synaptic plasticity, spontaneous activity
and neuronal oscillations in the adult BC. The decrease in the number of interneurons
increased basal synaptic transmission, as examined by recording field excitatory postsynaptic
potentials (fEPSPs) from layer II networks in the Rac1 cKO mouse cortex, decreased long-term
potentiation (LTP) in response to tetanic stimulation but did not alter the pair-pulse ratio
(PPR). Furthermore, under spontaneous recording conditions, Rac1 cKO brain slices exhibit
enhanced sensitivity and susceptibility to emergent spontaneous activity. We also found that
this developmental decrease in the number of cortical interneurons results in local neuronal
networks with alterations in neuronal oscillations, exhibiting decreased power in low
frequencies (delta, theta, alpha) and gamma frequency range (30-80Hz) with an extra
aberrant peak in high gamma frequency range (80-150Hz). Therefore, our data show that
disruption in GABAergic inhibition alters synaptic properties and plasticity, while it
additionally disrupts the cortical neuronal synchronization in the adult BC.